Sentinel cluster of locally acquired Japanese encephalitis in southern Australia.

Prior to January 2022, only a single case of infection with Japanese encephalitis virus (JEV) had been reported on the Australian mainland, acquired in the northern extremity on Cape York. We report the clinical characteristics of the sentinel cluster of cases that confirmed the local acquisition of JEV in southern Australia along the Murray River bordering New South Wales and Victoria.

Current Epidemiology and Clinical Features of Cryptococcus Infection in Patients Without Human Immunodeficiency Virus: A Multicenter Study in 46 Hospitals in Australia and New Zealand.

BACKGROUND: Patients without human immunodeficiency virus (HIV) are increasingly recognized as being at risk for cryptococcosis. Knowledge of characteristics of cryptococcosis in these patients remains incomplete. METHODS: We conducted a retrospective study of cryptococcosis in 46 Australian and New Zealand hospitals to compare its frequency in patients with and without HIV and describe its characteristics in patients without HIV. Patients with cryptococcosis between January 2015 and December 2019 were included. RESULTS: Of 475 patients with cryptococcosis, 90% were without HIV (426 of 475) with marked predominance in both Cryptococcus neoformans (88.7%) and Cryptococcus gattii cases (94.3%). Most patients without HIV (60.8%) had a known immunocompromising condition: cancer (n = 91), organ transplantation (n = 81), or other immunocompromising condition (n = 97). Cryptococcosis presented as incidental imaging findings in 16.4% of patients (70 of 426). The serum cryptococcal antigen test was positive in 85.1% of tested patients (319 of 375); high titers independently predicted risk of central nervous system involvement. Lumbar puncture was performed in 167 patients to screen for asymptomatic meningitis, with a positivity rate of 13.2% where meningitis could have been predicted by a high serum cryptococcal antigen titer and/or fungemia in 95% of evaluable cases. One-year all-cause mortality was 20.9% in patients without HIV and 21.7% in patients with HIV (P = .89). CONCLUSIONS: Ninety percent of cryptococcosis cases occurred in patients without HIV (89% and 94% for C. neoformans and C. gattii, respectively). Emerging patient risk groups were evident. A high level of awareness is warranted to diagnose cryptococcosis in patients without HIV.

Tuberculosis notifications in regional Victoria, Australia: Implications for public health care in a low incidence setting.

BACKGROUND: Regionality is often a significant factor in tuberculosis (TB) management and outcomes worldwide. A wide range of context-specific factors may influence these differences and change over time. We compared TB treatment in regional and metropolitan areas, considering demographic and temporal trends affecting TB diagnosis and outcomes. METHODS: Retrospective analyses of data for patients notified with TB in Victoria, Australia, were conducted. The study outcomes were treatment delays and treatment outcomes. Multivariable Cox proportional hazard model analyses were performed to investigate the effect of regionality in the management of TB. Six hundred and eleven (7%) TB patients were notified in regional and 8,163 (93%) in metropolitan areas between 1995 and 2019. Of the 611 cases in the regional cohort, 401 (66%) were overseas-born. Fifty-one percent of the overseas-born patients in regional Victoria developed TB disease within five years of arrival in Australia. Four cases of multidrug-resistant tuberculosis were reported in regional areas, compared to 97 cases in metropolitan areas. A total of 3,238 patients notified from 2012 to 2019 were included in the survival analysis. The time follow-up for patient delay started at symptom onset date, and the event was the presentation to the healthcare centre. For healthcare system delay, follow-up time began at the presentation to the healthcare centre, and the event was commenced on TB treatment. Cases with extrapulmonary TB in regional areas have a non-significantly longer healthcare system delay than patients in metropolitan (median 64 days versus 54 days, AHR = 0.8, 95% CI 0.6-1.0, P = 0.094). CONCLUSION: Tuberculosis in regional Victoria is common among the overseas-born population, and patients with extrapulmonary TB in regional areas experienced a non-significant minor delay in treatment commencement with no apparent detriment to treatment outcomes. Improving access to LTBI management in regional areas may reduce the burden of TB.

SARS-CoV-2 Seroprevalence in a Cohort of International Travellers Returning to Rural Australia: Enablers and Barriers to Containment of COVID-19.

OBJECTIVE: To describe the effectiveness of the public health response to COVID-19 in our local region by documenting detection of SARS-CoV-2 infection by nucleic acid testing (NAT) positivity and seroprevalence. METHODS: In this prospective study (ACTRN12620000487910), symptomatic adult international travellers returning to regional Australia in March 2020 underwent SARS-CoV-2 NAT and SARS-CoV-2-specific serology. RESULTS: Ninety-nine eligible participants were included. Nine participants had laboratory confirmed SARS-CoV-2, all returning between 16-20 March 2020. Eight (89%) had a positive NAT and seven (78%) had a positive serology test. The majority returned from New Zealand. Participants most frequently presented with cough (100%), headache (66.7%) and sore throat (44.4%). No community cases were detected from 1 March to 30 June 2020. CONCLUSIONS: The study cohort of international travellers returning to regional Australia in March 2020 returned eight positive SARS-CoV-2 NAT results over a five-day window. Serology identified one additional case and was negative in two cases who were PCR positive. Longitudinal data confirmed an absence of local community transmission to 30 June 2020. IMPLICATIONS FOR PUBLIC HEALTH: A combination of local, national and environmental factors were necessary to prevent the establishment of community transmission in our local region.

Preclinical Safety Assessment and Toxicokinetics of Apitegromab, an Antibody Targeting Proforms of Myostatin for the Treatment of Muscle-Atrophying Disease.

Myostatin is a negative regulator of skeletal muscle and has become a therapeutic target for muscle atrophying disorders. Although previous inhibitors of myostatin offered promising preclinical data, these therapies demonstrated a lack of specificity toward myostatin signaling and have shown limited success in the clinic. Apitegromab is a fully human, monoclonal antibody that binds to human promyostatin and latent myostatin with a high degree of specificity, without binding mature myostatin and other closely related growth factors. To support the clinical development of apitegromab, we present data from a comprehensive preclinical assessment of its pharmacology, pharmacokinetics, and safety across multiple species. In vitro studies confirmed the ability of apitegromab to inhibit the activation of promyostatin. Toxicology studies in monkeys for 4 weeks and in adult rats for up to 26 weeks showed that weekly intravenous administration of apitegromab achieved sustained serum exposure and target engagement and was well-tolerated, with no treatment-related adverse findings at the highest doses tested of up to 100 mg/kg and 300 mg/kg in monkeys and rats, respectively. Additionally, results from an 8-week juvenile rat study showed no adverse effects on any endpoint, including neurodevelopmental, motor, and reproductive outcomes at 300 mg/kg administered weekly IV. In summary, the nonclinical pharmacology, pharmacokinetic, and toxicology data demonstrate that apitegromab is a selective inhibitor of proforms of myostatin that does not exhibit toxicities observed with other myostatin pathway inhibitors. These data support the conduct of ongoing clinical studies of apitegromab in adult and pediatric patients with spinal muscular atrophy (SMA).

Posterior reversible encephalopathy syndrome in acute pancreatitis: a rare stroke mimic.

We report a 71-year-old woman who presented with Posterior Reversible Encephalopathy Syndrome (PRES) in the setting of acute pancreatitis. On day 3 of her admission, she developed transient right-sided upper and lower limb weakness, reduced visual acuity and encephalopathy, initially regarded as an acute stroke. Brain MRI fluid-attenuated inversion recovery (FLAIR) T2 imaging performed the same day confirmed occipital and parietal hyperdensities consistent with PRES. Her blood pressure never exceeded 150/75 mm Hg throughout the course of the admission. Our case demonstrates PRES in the setting of acute pancreatitis with only a relatively moderate elevation in blood pressure. In order to prevent unnecessary intervention in the setting of presumed acute stroke, it is important to consider the potential differential diagnoses including PRES as rare masquerade of acute stroke or transient ischaemic attack.

Selective inhibition of TGFß1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape.

Despite breakthroughs achieved with cancer checkpoint blockade therapy (CBT), many patients do not respond to anti-programmed cell death-1 (PD-1) due to primary or acquired resistance. Human tumor profiling and preclinical studies in tumor models have recently uncovered transforming growth factor-ß (TGFß) signaling activity as a potential point of intervention to overcome primary resistance to CBT. However, the development of therapies targeting TGFß signaling has been hindered by dose-limiting cardiotoxicities, possibly due to nonselective inhibition of multiple TGFß isoforms. Analysis of mRNA expression data from The Cancer Genome Atlas revealed that TGFΒ1 is the most prevalent TGFß isoform expressed in many types of human tumors, suggesting that TGFß1 may be a key contributor to primary CBT resistance. To test whether selective TGFß1 inhibition is sufficient to overcome CBT resistance, we generated a high-affinity, fully human antibody, SRK-181, that selectively binds to latent TGFß1 and inhibits its activation. Coadministration of SRK-181-mIgG1 and an anti-PD-1 antibody in mice harboring syngeneic tumors refractory to anti-PD-1 treatment induced profound antitumor responses and survival benefit. Specific targeting of TGFß1 was also effective in tumors expressing more than one TGFß isoform. Combined SRK-181-mIgG1 and anti-PD-1 treatment resulted in increased intratumoral CD8+ T cells and decreased immunosuppressive myeloid cells. No cardiac valvulopathy was observed in a 4-week rat toxicology study with SRK-181, suggesting that selectively blocking TGFß1 activation may avoid dose-limiting toxicities previously observed with pan-TGFß inhibitors. These results establish a rationale for exploring selective TGFß1 inhibition to overcome primary resistance to CBT.

Structural basis of specific inhibition of extracellular activation of pro- or latent myostatin by the monoclonal antibody SRK-015.

Myostatin (or growth/differentiation factor 8 (GDF8)) is a member of the transforming growth factor ß superfamily of growth factors and negatively regulates skeletal muscle growth. Its dysregulation is implicated in muscle wasting diseases. SRK-015 is a clinical-stage mAb that prevents extracellular proteolytic activation of pro- and latent myostatin. Here we used integrated structural and biochemical approaches to elucidate the molecular mechanism of antibody-mediated neutralization of pro-myostatin activation. The crystal structure of pro-myostatin in complex with 29H4-16 Fab, a high-affinity variant of SRK-015, at 2.79 Å resolution revealed that the antibody binds to a conformational epitope in the arm region of the prodomain distant from the proteolytic cleavage sites. This epitope is highly sequence-divergent, having only limited similarity to other closely related members of the transforming growth factor ß superfamily. Hydrogen/deuterium exchange MS experiments indicated that antibody binding induces conformational changes in pro- and latent myostatin that span the arm region, the loops contiguous to the protease cleavage sites, and the latency-associated structural elements. Moreover, negative-stain EM with full-length antibodies disclosed a stable, ring-like antigen-antibody structure in which the two Fab arms of a single antibody occupy the two arm regions of the prodomain in the pro- and latent myostatin homodimers, suggesting a 1:1 (antibody:myostatin homodimer) binding stoichiometry. These results suggest that SRK-015 binding stabilizes the latent conformation and limits the accessibility of protease cleavage sites within the prodomain. These findings shed light on approaches that specifically block the extracellular activation of growth factors by targeting their precursor forms.

A Sensitive and Selective Immunoassay for the Quantitation of Serum Latent Myostatin after In Vivo Administration of SRK-015, a Selective Inhibitor of Myostatin Activation.

Myostatin, a member of the transforming growth factor ß (TGFß) superfamily, is a key regulator of skeletal muscle mass and a therapeutic target for muscle wasting diseases. We developed a human monoclonal antibody, SRK-015, that selectively binds to and inhibits proteolytic processing of myostatin precursors, thereby preventing growth factor release from the latent complex. As a consequence of antibody binding, latent myostatin accumulates in the circulation of animals treated with SRK-015 or closely related antibodies, suggesting that quantitation of latent myostatin in serum may serve as a biomarker for target engagement. To accurately measure SRK-015 target engagement, we developed a sensitive plate-based electrochemiluminescent immunoassay to quantitate latent myostatin in serum samples. The assay selectively recognizes latent myostatin without cross-reactivity to promyostatin, mature myostatin, or closely related members of the TGFß superfamily. To enable use of the assay in samples from animals dosed with SRK-015, we incorporated a low-pH step that dissociates SRK-015 from latent myostatin, improving drug tolerance of the assay. The assay meets inter- and intra-assay accuracy and precision acceptance criteria, and it has a lower limit of quantitation (LLOQ) of 10 ng/mL. We then tested serum samples from a pharmacology study in cynomolgus monkeys treated with SRK-015. Serum latent myostatin increases after treatment with SRK-015, reaches a dose-dependent plateau approximately 20 days after dosing, and trends back toward baseline after cessation of antibody dosing. Taken together, these data suggest that this assay can be used to accurately measure levels of the primary circulating form of myostatin in population-based or pharmacodynamic studies.

Brainstem stroke caused by left atrial cardiac papillary fibroelastoma: an increasingly recognized rare cause of stroke.

Cardiac papillary fibroelastoma is a rare but increasingly recognized cause of embolic stroke that is prevalent in the older population and requires prompt surgical management. We report an unusual case of left atrial appendage cardiac fibroelastoma in a 76-year-old gentleman who presented with left internuclear ophthalmoplegia and ataxia, with corresponding diffusion-weighted imaging on magnetic resonance imaging of the brain. This case illustrates the importance of echocardiographic imaging in the workup of cardioembolic stroke in the older adult population in the acute setting.

Randomized controlled trial of a positive affect intervention for methamphetamine users.

BACKGROUND: Contingency management (CM) is an evidence-based intervention providing rewards in exchange for biomarkers that confirm abstinence from stimulants such as methamphetamine. We tested the efficacy of a positive affect intervention designed to boost the effectiveness of CM with HIV-positive, methamphetamine-using sexual minority men. METHODS: This attention-matched, randomized controlled trial of a positive affect intervention delivered during CM was registered on www.clinicaltrials.gov (NCT01926184). In total, 110 HIV-positive sexual minority men with biologically confirmed, recent methamphetamine use were enrolled. Five individual sessions of a positive affect intervention (n = 55) or an attention-control condition (n = 55) were delivered during three months of CM. Secondary outcomes examined over the 3-month intervention period included: 1) psychological processes relevant to affect regulation (i.e., positive affect, negative affect, and mindfulness); 2) methamphetamine craving; 3) self-reported stimulant use (past 3 months); and 4) cumulative number of urine samples that were non-reactive for stimulants (i.e., methamphetamine and cocaine) during CM. RESULTS: Those randomized to the positive affect intervention reported significant increases in positive affect during individual sessions and increases in mindfulness over the 3-month intervention period. Intervention-related improvements in these psychological processes relevant to affect regulation were paralleled by concurrent decreases in methamphetamine craving and self-reported stimulant use over the 3-month intervention period. CONCLUSIONS: Delivering a positive affect intervention may improve affect regulation as well as reduce methamphetamine craving and stimulant use during CM with HIV-positive, methamphetamine-using sexual minority men.

Tolloid cleavage activates latent GDF8 by priming the pro-complex for dissociation.

Growth differentiation factor 8 (GDF8)/myostatin is a latent TGF-ß family member that potently inhibits skeletal muscle growth. Here, we compared the conformation and dynamics of precursor, latent, and Tolloid-cleaved GDF8 pro-complexes to understand structural mechanisms underlying latency and activation of GDF8. Negative stain electron microscopy (EM) of precursor and latent pro-complexes reveals a V-shaped conformation that is unaltered by furin cleavage and sharply contrasts with the ring-like, cross-armed conformation of latent TGF-ß1. Surprisingly, Tolloid-cleaved GDF8 does not immediately dissociate, but in EM exhibits structural heterogeneity consistent with partial dissociation. Hydrogen-deuterium exchange was not affected by furin cleavage. In contrast, Tolloid cleavage, in the absence of prodomain-growth factor dissociation, increased exchange in regions that correspond in pro-TGF-ß1 to the α1-helix, latency lasso, and ß1-strand in the prodomain and to the ß6'- and ß7'-strands in the growth factor. Thus, these regions are important in maintaining GDF8 latency. Our results show that Tolloid cleavage activates latent GDF8 by destabilizing specific prodomain-growth factor interfaces and primes the growth factor for release from the prodomain.

Infections, resistance patterns and antibiotic use in patients at a regional cancer centre.

BACKGROUND: Infections and antibiotic resistance patterns in patients attending regional Australian cancer centres are poorly described. AIMS: To document patient characteristics, infection types, patterns of antibiotic resistance and outcomes in all patients with cancer requiring inpatient management for suspected infection at a regional Australian cancer centre. METHODS: We studied patients ≥18 years of age who were admitted under the oncology unit at Albury Wodonga Health during a 12-month period and who had a microbiological test performed for suspected infection during their admission. Data were extracted retrospectively from electronic records and analysed through descriptive statistics. RESULTS: We identified 275 episodes of suspected infection occurring in 208 patients (M/F: 61%/39%). Median age was 68 years, solid tumour 76%, haematological malignancy 24%. A positive culture was obtained in 28% of cases: Gram-positive 48.5% and Gram-negative 51.5%. Drug resistant Pseudomonas aeruginosa was seen in 38% (5/13) of pseudomonas isolates, three times the rate seen in general hospital admissions. Extended spectrum beta lactamase was seen in 22% of Gram-negative isolates. Empiric IV antibiotic choice was guideline concordant in 61% of neutropenic fever (NF) (NF) presentations. Only 17% of NF presentations received antibiotics within the recommended hour of emergency department triage. The inpatient mortality rate was 3%. Fifty-seven percent of NF presentations satisfied Multinational Association of Supportive Care in Cancer risk index criteria for outpatient management. CONCLUSIONS: This is the first study of this type in patients with cancer at an Australian regional cancer centre. The study highlighted key areas for improvement in antibiotic prescription and control of antibiotic resistance at our institution.

Supervised exercise improves cutaneous reinnervation capacity in metabolic syndrome patients.

OBJECTIVE: Unmyelinated cutaneous axons are vulnerable to physical and metabolic injury, but also capable of rapid regeneration. This balance may help determine risk for peripheral neuropathy associated with diabetes or metabolic syndrome. Capsaicin application for 48 hours induces cutaneous fibers to die back into the dermis. Regrowth can be monitored by serial skin biopsies to determine intraepidermal nerve fiber density (IENFD). We used this capsaicin axotomy technique to examine the effects of exercise on cutaneous regenerative capacity in the setting of metabolic syndrome. METHODS: Baseline ankle IENFD and 30-day cutaneous regeneration after thigh capsaicin axotomy were compared for participants with type 2 diabetes (n = 35) or metabolic syndrome (n = 32) without symptoms or examination evidence of neuropathy. Thirty-six participants (17 with metabolic syndrome) then joined twice weekly observed exercise and lifestyle counseling. Axotomy regeneration was repeated in month 4 during this intervention. RESULTS: Baseline distal leg IENFD was significantly reduced for both metabolic syndrome and diabetic groups. With exercise, participants significantly improved exercise capacity and lower extremity power. Following exercise, 30-day reinnervation rate improved (0.051 ± 0.027 fibers/mm/day before vs 0.072 ± 0.030 after exercise, p = 0.002). Those who achieved improvement in more metabolic syndrome features experienced a greater degree of 30-day reinnervation (p < 0.012). INTERPRETATION: Metabolic syndrome was associated with reduced baseline IENFD and cutaneous regeneration capacity comparable to that seen in diabetes. Exercise-induced improvement in metabolic syndrome features increased cutaneous regenerative capacity. The results underscore the potential benefit to peripheral nerve function of a behavioral modification approach to metabolic improvement.

Exercise increases cutaneous nerve density in diabetic patients without neuropathy.

Early diabetic neuropathy is characterized by loss of unmyelinated axons, resulting in pain, numbness, and progressive decline in intraepidermal nerve fiber density. Patients with type 2 diabetes, without neuropathy, were assigned to quarterly lifestyle counseling (N = 40) or structured, supervised weekly exercise (N = 60) for 1 year. Distal leg IENFD significantly increased in the exercise cohort and remained unchanged in the counseling cohort (1.5 ± 3.6 vs. -0.1 ± 3.2 fibers/mm, P = 0.03). These results suggest preclinical injury to unmyelinated axons is potentially reversible, and that IENFD may be a responsive biomarker useful in future neuropathy prevention clinical trials.

Aminoglycosides: how should we use them in the 21st century?

PURPOSE OF REVIEW: Aminoglycoside antibiotics (AGAs) have proved an invaluable part of our antimicrobial armamentarium since their introduction into practice over 60 years ago. This review summarizes recent developments, defining their role in the context of the current global epidemic of antibiotic resistance, raising awareness of their toxicity profile, and highlighting current data on their utility as synergistic agents. RECENT FINDINGS: Clinicians are facing an unprecedented threat from antibiotic resistance, resulting in an increased reliance on the addition of an AGA to provide adequate empirical cover in cases of severe sepsis. Concurrently, an increased awareness of the potential for severe disability, particularly from vestibular toxicity, has restrained directed therapy of AGAs to situations in which there are no appropriate alternatives. Their role as synergistic agents in the treatment of enterococcal endocarditis is currently under reevaluation, and new data have emerged on combination therapy for Pseudomonas aeruginosa bacteremia. AGAs are themselves coming under increasing threat from resistance, predominately from aminoglycoside modifying enzymes (mediating selective resistance) and 16S rRNA methyltransferases (conferring class-wide resistance). New agents and the development of alternate ways to circumvent resistance are likely to have important roles in future clinical care. SUMMARY: Aminoglycosides retain an invaluable but well defined role, and will remain important agents into the foreseeable future.

Feasibility and promise of a remote-delivered preconception motivational interviewing intervention to reduce risk for alcohol-exposed pregnancy.

BACKGROUND: Alcohol-exposed pregnancy (AEP) is a leading cause of birth defects. Effective face-to-face preconception interventions based on motivational interviewing (MI) exist and should be translated into remote formats for maximum public health impact. This study investigated the feasibility and promise of a one-session, remote-delivered, preconception, MI-based AEP intervention (EARLY Remote) for non-treatment-seeking community women. SUBJECTS AND METHODS: This was a single-arm, prospective pilot intervention study. All participants received the intervention via telephone and mail. Feasibility of remote-delivery methods, treatment engagement, treatment credibility, MI treatment integrity, and therapeutic alliance were examined. Outcomes were 3- and 6-month drinks per drinking day (DDD), rate of unreliable contraception, and proportion of women at risk for AEP due to continued risk drinking and no or unreliable contraception use. RESULTS: Feasibility of remote delivery was established; participants were engaged by the intervention and rated it as credible. Integrity to MI and therapeutic alliance were good. Both DDD and rate of unreliable contraception decreased significantly over time. Proportions of women who drank at risk levels, used unreliable or no contraception, and/or were at risk for AEP in the past 90 days decreased significantly from baseline to 6 months. CONCLUSIONS: Remote delivery was feasible, and the translated remote intervention may reduce AEP risk. Refinement of EARLY Remote may facilitate its placement within a spectrum of effective MI-based preconception AEP interventions as part of a stepped-care approach. EARLY Remote may have an important role within a stepped-care model for dissemination to geographically disperse women at risk for AEP. This could result in substantial public health impact through reduction of AEP on a larger scale.

Francisella tularensis subspecies holarctica, Tasmania, Australia, 2011.

We report a case of ulceroglandular tularemia that developed in a woman after she was bitten by a ringtail possum (Pseudocheirus peregrinus) in a forest in Tasmania, Australia. Francisella tularensis subspecies holarctica was identified. This case indicates the emergence of F. tularensis type B in the Southern Hemisphere.